It is recognized that hypertension can be a consequence of various types of renal dysfunction but the impact of elevated blood pressure upon the development of renal injury remains poorly understood. We hypothesize that elevations of renal perfusion pressure can be an important cause of renal injury, starting first in the renal outer medulla. The proposed studies will explore the consequences of the direct effects of elevated arterial pressure upon renal injury in Sprague Dawley rats and focus on three important questions: 1) What are the direct contributions of chronic elevations of renal perfusion pressure to tissue injury in the renal cortex and outer medulla; 2) To what extent is the renal vulnerability to pressure-induced injury correlated to systemic factors (such as angiotensin II and norepinephrine) and the local balance between reactive oxygen species and nitric oxide in the kidney; 3) What is the role of hydrogen peroxide (H2O2) as a key mediator of the pressure-induced injury? Novel servo-control techniques will be used that enable pressure to the left kidney to be maintained at a normal level during the development of hypertension while the contralateral right kidney is exposed chronically to elevated pressure. Different states of vulnerability to pressure-induced injury will be produced using three models of hypertension (Specific Aims 1-3). Aim 4 determines the role of H2O2 in pressure-induced injury to the renal medulla by infusing catalase into the medulla of the left kidney during the development of angiotensin lI+L-NAME-induced hypertension and conversely by infusing H2O2 into the left kidney of normal rats. Renal injury in each of the Aims will be assessed at three time points during the development of hypertension (days 3, 7 and 14) using techniques of microdialysis to collect interstitial fluid for the determination of H2O2 and nitric oxide concentrations. Renal tissue will be collected and protein expression and enzyme activities related to the pathways of synthesis and degradation of these reactive oxygen species measured. Histological techniques and immunostaining will be utilized to quantify the degree of tissue injury. The results of the proposed studies should significantly advance our understanding of the impact of blood pressure upon the development of renal interstitial fibrosis and tubuloglomerular injury in hypertension and the role of oxidative stress in this process. An understanding of these mechanisms could lead to new therapeutic approaches for the prevention of kidney disease in hypertension.